Generalizing Intensive Blood Pressure Treatment to Adults With Diabetes Mellitus

Abstract

Background:

Controversy over blood pressure treatment targets for individuals with diabetes is in part due to conflicting perspectives about generalizability of available trial data.

Objective:

To estimate how results from the largest clinical trial of intensive blood pressure treatment among adults with diabetes would generalize to the U.S. population.

Methods:

We used transportability methods to re-weight individual patient data from the ACCORD BP trial (n=4507) of intensive (goal systolic blood pressure [SBP] < 120 mm Hg) vs. standard (goal SBP <140 mm Hg) treatment to better represent the demographic and clinical risk factors of U.S. population of adults with diabetes (data from NHANES 2005-2014, n=1943). The primary outcome was the first occurrence of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. Analysis used weighted Cox proportional hazards regression models with robust standard errors.

Results:

The ACCORD BP sample had less racial/ethnic diversity and more elevated cardiovascular risk factors than NHANES participants. Weighted results significantly favored intensive BP treatment, unlike unweighted results (hazard ratio [HR] for primary outcome in intensive versus standard treatment in weighted analyses: 0.67, 95% confidence interval [95%CI] 0.49 to 0.91; in unweighted analyses: HR 0.88, 95%CI 0.73 to 1.07). Over 5 years, the weighted results estimate a number needed to treat of 34, and number needed to harm of 55.

Conclusions:

After re-weighting to better reflect the U.S. adult population with diabetes, intensive BP therapy was associated with significantly lower risk for cardiovascular events. However, data were limited among racial/ethnic minorities and those with lower cardiovascular risk.

Condensed Abstract

The appropriate blood pressure treatment target for individuals with diabetes remains unclear, in part due to conflicting perspectives about the generalizability of available trial data. The largest trial of intensive blood pressure control in individuals with diabetes, ACCORD BP, found no benefit of intensive control, but may not have been representative of the U.S. population of individuals with diabetes. We used transportability methods to re-weight the ACCORD BP results to better reflect the real-world distribution of clinical and social risk factors. We found that intensive blood pressure treatment was associated with reduced cardiovascular events in weighted analyses.

Central Illustration:

Conceptual illustration of transportability method and impact on the results Central Illustration Caption: The top panel is a conceptual illustration that represents re-weighting a distribution of covariates in a sample study in order to better match the distribution of covariates in a target population. The lower panels plot the Kaplan-Meier estimates of experiencing the ACCORD BP primary outcome (a composite of first occurrence of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death), in the unweighted (left) and weighted (right) analyses.

Introduction

Uncontrolled blood pressure remains a leading cause of excess cardiovascular morbidity and mortality among patients with diabetes mellitus (DM).(1) Determining the appropriate blood pressure (BP) control target is of major clinical and public health importance. However, the BP targets to adopt for this population remain controversial, with conflicting recommendations from different guideline-issuing groups. The 2017 update of the American Heart Association/American College of Cardiology BP treatment guidelines(2) recommend universal intensive BP treatment for adults with DM (target BP: < 130/80 mm Hg). The 2018 Standards of Care in Diabetes from the American Diabetes Association, however, recommend a target of <140/90 mm Hg for most patients.(3) Similarly, the American College of Physicians and the American Academy of Family Physicians have not endorsed the AHA/ACC hypertension guidelines for individuals with DM.(4) The differences among guidelines leave individual practitioners and patients with a dilemma when deciding on a target BP.

The differences among current guidelines largely result from different interpretations of how to generalize two large randomized trials. The Systolic Blood Pressure Intervention Trial (SPRINT) trial(5) enrolled high-risk individuals without DM to intensive vs. standard blood pressure control (systolic target: < 120 versus <140 mm Hg) and found a 27% reduction in mortality for intensive BP treatment. Yet the largest randomized clinical trial of intensive BP treatment among people with DM, the Action to Control Cardiovascular Risk in Diabetes - Blood Pressure (ACCORD BP) trial did not find significant benefit of intensive BP treatment for its primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes; HR 0.88, 95% CI 0.73 - 1.06).(6) Further, participants in the intensive BP treatment arm of ACCORD BP experienced more serious adverse events related to BP medications than participants in the standard arm (serious adverse event rate 3.3% vs. 1.3%, p<0.0001).(6)

A new possibility to inform clinical decisions in the presence of conflicting trial results is to quantitatively assess the generalizability of a trial to the population of patients among whom the clinical decision is meant to apply. Recent advances in statistical approaches called “transportability methods” allow us to quantify how the results of the ACCORD BP trial may generalize to the broader U.S. population of patients with DM, and specifically estimate how much the general population might experience different outcomes from intensive BP treatment than the result seen in the ACCORD BP trial.(7-11) Transportability methods can be thought of as re-weighting the results from each member of the trial sample to construct a pseudopopulation that matches the demographics and clinical characteristics of the broader national population with DM. By weighting the trial results, the overall effectiveness of intensive BP treatment for the more general population can be estimated, helping to inform whether individual practitioners may be wary or eager to implement intensive BP treatment among patients with DM.

Here, we sought to identify how the ACCORD BP study results may be generalized to people with DM in the United States, and thereby inform recommendations

Methods

Source of Data and Sample Size

Individual patient data from the ACCORD BP trial (N=4507)(6), and individual-level data pooled from repeated cross-sections of the National Health and Nutrition Examination Survey (NHANES, 2005-2014, N = 1943), a nationally-representative population-based epidemiologic surveillance study of non-institutionalized Americans(12) were used to conduct the study. Analyses incorporated NHANES design information, including sampling weights and clustering, as appropriate. We did not use data from the SPRINT trial in this study because SPRINT did not include individuals with DM, and thus data on several relevant cardiovascular risk factors for individuals with diabetes was not measured. Further, SPRINT did not release socioeconomic status information that would be used for transportability estimates.(5)

Participants

ACCORD BP

Detailed information on the study design and main outcomes of ACCORD BP were previously published.(6) In brief, ACCORD enrolled 10,251 type 2 diabetes patients with a history of a hemoglobin A1c (HbA1c) > 7.5%, and cardiovascular disease (if age > 40 years) or high cardiovascular risk (if age > 55 years) to an intensive vs. standard glycemic control strategy. Using a 2×2 factorial design, patients were additionally assigned to either a lipid-lowering study (the ACCORD lipid trial) or a blood pressure lowering study (ACCORD BP, n=4733). Additional entry criteria for the ACCORD BP trial are described in the study protocol (https://biolincc.nhlbi.nih.gov/static/studies/accord/Protocol.pdf), but include having a systolic blood pressure between 130 and 180 mm Hg on three or fewer blood pressure lowering medications, and urinary protein excretion less than 1.0g in 24 hours. Participants in the ACCORD BP trial were randomly assigned to the intensive blood pressure treatment (n=2362; goal systolic blood pressure [SBP] < 120 mm Hg; achieved mean SBP after 1 year 119.3 mm Hg) or standard blood pressure treatment (n=2371; goal SBP <140 mm Hg; achieved mean SBP after 1 year 133.5 mm Hg) arm. Treatment was not blinded, and strategy for achievement of that the treatment goal (e.g. choice of medications and dose adjustment) was determined by individual study physicians under broad guidance. The maximum duration of follow-up was 7 years.

NHANES

To determine the sociodemographic and clinical characteristics of the civilian U.S. population of patients with diabetes mellitus, we used demographic, questionnaire, examination, and fasting laboratory data from NHANES (https://wwwn.cdc.gov/nchs/nhanes/Default.aspx) pooled across 10 years (2005-2014), which incorporates the most recent data available. As in prior studies, diabetes mellitus was defined as patient self-report of a diagnosis of diabetes, hemoglobin A1c > 6.5%, or fasting plasma glucose > 126 mg/dL.(13-15) We did not distinguish between type 1 and type 2 diabetes in this study, as current BP guidelines do not. Because current guidelines are meant to apply to adults, we included NHANES participants aged ≥ 20 years, and because separate guidelines exist for management of blood pressure in pregnancy, we excluded those currently pregnant. Because we were concerned that data within NHANES may not distinguish between those with controlled hypertension from those without hypertension, we did not have explicit hypertension-related inclusion criteria in our main analyses. However, to investigate whether this decision could affect the results, we performed two sensitivity analyses. In the first, in addition to the above criteria we also required a self-report of hypertension diagnosis, a self-report of taking a blood pressure lowering medication, a systolic blood pressure measurement (averaged over all NHANES measurements) of > 130 mm Hg, or a diastolic blood pressure measurement (averaged over all NHANES measurements) of > 80 mm Hg.(2) The second sensitivity analysis sample required that systolic blood pressure (averaged over all NHANES measurements) be between 130 and 180 mm Hg, which closely matches an ACCORD BP eligibility criterion.(6)

Outcomes

The outcomes for this study matched those of the ACCORD BP trial. The primary outcome was a composite of first occurrence of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. Secondary outcomes used in this study were all-cause mortality, total (fatal and non-fatal) stroke, the main microvascular composite outcome from ACCORD (first occurrence of renal failure [initiation of dialysis or ESRD, renal transplantation, or rise of serum creatinine >291.72 micromol/L] or retinal photocoagulation or vitrectomy to treat retinopathy), and number of serious non-hypoglycemic adverse events (defined as hypotension, syncope, bradycardia or arrhythmia, hyperkalemia, or renal failure, attributable to the study medication).(6)

Factors used for weighting

We considered several potential effect modifiers that may alter the risk or benefit of intensive vs. standard blood pressure treatment. These factors were selected on the basis of prior evidence or hypotheses for their association with cardiovascular disease risk.(3, 16-20) The factors considered were: age, gender, race/ethnicity (categorized as non-Hispanic white, non-Hispanic black, Hispanic, and Other/Multi-racial), education (categorized as less than high school diploma, high school diploma, some college, or college degree and higher), health insurance status (insured/uninsured), tobacco smoking status (never, current, former), history of myocardial infraction (MI), history of congestive heart failure (CHF), history of stroke, systolic blood pressure, diastolic blood pressure, total cholesterol, high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), triglycerides, hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), glomerular filtration rate (GFR) (estimated using the 4-term modification of diet in renal disease [MDRD] equation), urinary albumin to creatinine ratio, and body mass index (BMI; Table 1). All potential effect modifier measurements from the ACCORD BP study were taken from baseline (pre-treatment) examinations. Data from ACCORD BP and NHANES were inspected for implausible values, but only a small number of diastolic blood pressure readings < 30 mm Hg from NHANES were identified and excluded from the analysis.

Table 1:

Demographic and Clinical Characteristics of NHANES and ACCORD Participants, before and after weighting

	ACCORD before weighting	p	ASD	NHANES	ACCORD after weighting	p	ASD
	Mean (sd) or %			Mean (sd) or %	Mean (sd) or %
N	4507			1943, representing 26,733,959	4507
Baseline Age	62.76 (6.70)	<0.001	0.30	59.65 (13.70)	60.87 (6.59)	0.002	0.13
Female	47.4	0.42	0.03	48.8	48.4	0.87	0.01
Race/ethnicity		<0.001	0.34			<0.001	0.34
Non-Hispanic White	58.9			61.8	45.5
Non-Hispanic Black	23.9			15.3	19.6
Hispanic	6.9			15.4	25.5
Asian/Multi/Other	10.4			7.5	9.4
Education		<0.001	0.29			<0.001	0.20
< HS	16.2			26.8	31.9
HS Diploma	26.8			27.0	19.1
Some College	32.5			29.1	29.1
College Diploma or >	24.5			17.1	19.9
Insured	84.6	0.91	0.07	86.8	84.9	0.18	0.06
Smoking Status		<0.001	0.18			0.03	0.11
Never	44.9			51.1	56.7
Current	13.1			15.4	13.6
Former	42.0			33.4	29.7
Hx of CHF	4.3	<0.001	0.19	9.0	11.1	0.26	0.07
Hx of MI	13.8	0.002	0.10	10.5	11.0	0.68	0.02
Hx of Stroke	6.4	0.02	0.08	8.4	7.9	0.70	0.02
Years with diabetes	10.86 (7.84)	<0.001	0.38	7.49 (9.19)	10.53 (7.56)	<0.001	0.35
BMI, kg/m2	32.16 (5.46)	0.003	0.11	32.80 (7.30)	32.62 (5.87)	0.37	0.04
SBP, mm Hg	139.23 (15.83)	<0.001	0.51	130.08 (19.15)	132.93 (15.04)	<0.001	0.16
DBP, mm Hg	76.01 (10.35)	<0.001	0.62	69.51 (12.96)	71.88 (10.05)	<0.001	0.31
FPG, mg/dL	174.90 (57.82)	<0.001	0.33	151.87 (54.57)	180.23 (66.36)	<0.001	0.39
HbA1c, %	8.34 (1.09)	<0.001	0.78	7.16 (1.64)	8.07 (1.03)	<0.001	0.59
HDL, mg/dL	46.16 (13.64)	<0.001	0.15	49.11 (13.45)	50.87 (16.36)	<0.001	0.17
LDL, mg/dL	109.93 (36.75)	<0.001	0.16	103.86 (36.02)	105.44 (34.10)	0.41	0.04
Triglycerides, mg/dL	193.70 (176.29)	0.001	0.11	148.89 (76.09)	127.11 (68.86)	<0.001	0.35
Estimated GFR, mL/min	91.54 (28.93)	<0.001	0.15	87.46 (28.09)	84.12 (21.68)	0.003	0.12
Urine albumin to creatinine ratio	93.15 (326.11)	0.63	0.02	75.41 (481.22)	197.62 (739.92)	0.004	0.17

Means and percentages for NHANES are nationally-representative using NHANES sampling weights and clustering variables. P and ASD values are in comparison to NHANES. ASD = Absolute standardized difference. HS = high school. CHF = congestive heart failure. MI = history of myocardial infarction. BMI = body mass index. SBP = systolic blood pressure. DBP = diastolic blood pressure. FPG = fasting plasma glucose. HbA1c = hemoglobin a1c. GRF = glomerular filtration rate, estimated by the modification of diet in renal disease equation. HDL = high-density lipoprotein cholesterol. LDL = low-density lipoprotein cholesterol.

Missing Data

Missing data were not imputed because missingness was < 5% for any variable.

Statistical Analysis

To generalize the ACCORD BP results to the NHANES population (i.e., to “transport” the results from ACCORD BP to NHANES), we used a stabilized inverse odds of selection weighting approach that is analogous to propensity score weighting.(8) The intuition behind this approach is to up-weight individuals in ACCORD BP who have characteristics that are more common in NHANES, and down-weight those in ACCORD BP with characteristics less common in NHANES (Central Illustration). To calculate the weights, the probability of not being included in ACCORD was calculated for each person in NHANES, conditional on the above covariates, divided by their individual probability of being in ACCORD, conditional on the above covariates. The odds were then multiplied by a stabilization factor, which was the unconditional probability of being included in ACCORD divided by the unconditional probability of not being included. In mathematical terms, the stabilized inverse odds of selection were

$$\left(1-p|Z\right)/\left(p|Z\right)*\left(p/1-p\right)$$

where p is the probability of selection and Z is the vector of individual covariates. To estimate the conditional probability of selection, we fit a logistic regression model (eTable 1) with the outcome of being in ACCORD and the above covariates; NHANES sampling weights were then multiplied by the calculated selection weights to generate a nationally-representative population. The unconditional probability of selection was based on a null (intercept-only) logistic regression model, again incorporating NHANES weights. As a robustness check, we re-estimated the probabilities using a machine learning approach that can capture non-linearity between covariates and the outcome and complex interactions among covariates in a more sophisticated manner than standard logistic regression (see Technical Appendix).(21) Weights were Winsorized at the 2.5 and 97.5 percentiles to reduce the impact of extreme weights.(22, 23)

Outcome metrics

We calculated outcome metrics on both relative and absolute scales. For results on a relative scale, we used the same analytic approach as the main ACCORD BP analysis, fitting proportional hazard (Cox) regression models that contain terms for intensive vs. standard BP treatment, adjusting for intensive vs. standard glycemic treatment arm, clinical center, and previous history of cardiovascular event.(6) A previous study revealed that the proportional hazards assumption was reasonable in ACCORD BP.(6) We present unweighted results, which replicate the results of the main ACCORD BP manuscript as a check on our analysis, and results weighted by the inverse odds of selection to produce estimates transported to the NHANES population. Because the version of the ACCORD data available to us provides counts of serious adverse events rather than exact time-to-event data (to protect confidentiality), we used unweighted and weighted negative binomial models, offset by the person-time of follow-up for all-cause mortality, to model serious adverse events. Robust standard errors with independent covariance structure were estimated to calculate 95% confidence intervals.

For results on the absolute scale, we calculated number of events per 1000 person-years of follow-up, and plotted the survival function for time-to-event outcomes using Kaplan-Meier methods. We applied log-rank tests for significance of time-to-event outcomes, and the Wilcoxon two sample test (Mann-Whitney-U test) for serious adverse events with a design correction factor for weighted analyses.

Sensitivity and robustness checks

First, we conducted Cox/negative binomial regression analyses adjusting for factors that had an absolute standardized difference > 0.2 after weighting, to correct for residual imbalance between the weighted ACCORD BP population and the NHANES population. Second, we repeated analyses using a targeted maximum likelihood estimation approach, which has been shown to be less sensitive to positivity violations (cases where some combinations of important covariates are not observed in both the ACCORD BP and NHANES datasets).(9, 10) Next, we fit nested conditional probability models to identify combinations of characteristics that might be responsible for differences in transported and un-transported treatment effects. These models sequentially added subsets of the full set of cardiovascular risk factors based on imbalance between the ACCORD BP sample and the overall population. Finally, we fit the same weighted proportional hazards models in samples that additionally required hypertension-related inclusion criteria, as described above, to be met.

All analyses followed the intention-to-treat principle for treatment group assignment. A two-sided p-value < 0.05 was taken to indicate statistical significance. Analyses were conducted in SAS 9.4 (Cary, NC) (PROC LOGISTIC and PROC PHREG) and R 3.4.2 (Vienna, Austria). Statistical code for replication is available from the authors.

The human research committee at Partners Healthcare approved this study of secondary data.

Results

Study participant characteristics

Overall, 4507 participants from the ACCORD BP study were included, consisting of 2261 in the intensive treatment arm and 2246 in the standard arm. The median follow-up time for the primary outcome was 4.92 years. There were 1943 adults with diabetes included from the NHANES dataset. Comparisons between ACCORD BP and NHANES participants revealed significant differences between the study groups. In particular, ACCORD BP participants had less racial/ethnic diversity, greater education, and more elevated cardiovascular risk factors than the overall population (Table 1).

Transported results from ACCORD BP to NHANES

After weighting the ACCORD BP population to NHANES, the weighted ACCORD BP sample was more representative of the overall population, but, as would be expected by the study design, some imbalances remained, particularly in terms of racial/ethnic diversity, HbA1c, fasting plasma glucose, and duration of diabetes (Table 1). In general, weighting increased the proportion of individuals who were Hispanic, and those who had lower HbA1c, fasting glucose, and shorter duration of diabetes along with other changes as indicated in Table 1. The weights ranged from 0.01 to 4.67 (eFigure 1).

In analyses examining the primary outcome, weighted results favored intensive BP treatment, unlike the unweighted results (HR for the primary outcome in intensive versus standard treatment in weighted analyses 0.67, 95% confidence interval [95%CI] 0.49 to 0.91) (Table 2). In absolute terms, the transported results would indicate 14.4 cardiovascular events in the intensive BP treatment arm versus 20.2 in the standard arm per 1000 person-years (p=.03), with a number needed to treat of 172 over 1 year and 34 over 5 years to avert one cardiovascular event (Table 3). These contrast with the unweighted results of 21.27 events per 1000 person-years in the standard arm and 18.98 in the intensive arm (p=0.24).

Table 2:

Relative Risk of Outcomes for Intensive versus Standard Blood Pressure Therapy

	Unweighted		Weighted
	HR/IRR	95% CI	HR/IRR	95% CI
Primary Outcome	0.88	0.73 - 1.07	0.67	0.49 - 0.91
Total Mortality	1.07	0.85 - 1.35	0.91	0.62 - 1.32
Stroke	0.59	0.39 - 0.89	0.33	0.17 - 0.62
Microvascular Outcome	1.07	0.90 - 1.27	1.00	0.75 - 1.33
Serious Adverse Events	1.93	1.37 - 2.72	1.97	1.09 - 3.58

All estimates represent hazard ratios (HR) and 95% confidence intervals (CI) from proportional hazards regression models except for serious adverse events which represents incidence rate ratios from negative binomial models. Models are adjusted for intensive versus standard glycemic therapy, clinical network, and history of cardiovascular disease at baseline.

Table 3:

Absolute Differences in Outcomes for Intensive versus Standard Blood Pressure Treatment

		Unweighted			Weighted
		Events per 1000 person- years	Difference	P	Events per 1000 person- years	Difference	P
Primary Outcome
	Standard	21.27	−2.29	0.24	20.18	−5.77	0.03
	Intensive	18.98			14.40
Total Mortality
	Standard	12.15	0.83	0.50	11.82	−0.80	0.72
	Intensive	12.99			11.02
Stroke
	Standard	5.41	−2.20	0.01	5.42	−3.68	0.002
	Intensive	3.21			1.74
Microvascular
	Standard	24.50	2.00	0.41	26.80	−0.01	0.98
	Intensive	26.50			26.79
Serious Adverse Events
	Standard	4.47	4.18	0.0003	3.41	3.64	0.01
	Intensive	8.66			7.04

P-values from log rank test, except for serious adverse events, which used Wilcoxon. Weighted analyses used design-corrected versions

In the weighted analyses, total mortality (HR 0.91, 95%CI 0.62 to 1.32) was not different between intensive and standard therapy groups, nor was the risk of microvascular events (HR 1.00 95%CI 0.75 to 1.33). Stroke outcomes favored intensive therapy (HR 0.33 95%CI 0.17 to 0.62), showing more favorable point estimates in weighted versus unweighted analyses (unweighted HR 0.59, 95%CI 0.39-0.89). Weighted and unweighted Kaplan-Meier plots showing absolute outcome metrics for the time to event outcomes are presented in eFigures 2-9 and were consistent with the relative outcome metrics. Serious adverse events were more common in the weighted intensive therapy group (incidence rate ratio [IRR] 1.97 95% 1.09 to 3.58, number need to harm of 275 at 1 year or 55 at 5 years), and the estimate was similar to that of the unweighted analyses (unweighted IRR 1.93, 95%CI 1.37-2.72).

In sensitivity analyses that adjusted for residually imbalanced factors (race/ethnicity, education, diastolic blood pressure, fasting plasma glucose, HbA1c, triglycerides, and years with diabetes), point estimates were more strongly in favor of intensive BP therapy than in the weighted but unadjusted analyses (eTable 3), though adjustment did not produce any qualitative changes. In sensitivity analyses additionally requiring hypertension diagnosis or elevated blood pressure as inclusion criteria, estimates were similar to the main analyses (eTables 4-5). In sensitivity analyses using targeted maximum likelihood estimation, estimates were again more strongly in favor of intensive BP therapy (eTable 6). In analyses using nested models, weighting for demographic factors or clinical risk factors only did not fully explain the differences between unweighted and weighted results, but the combination of demographic and clinical factors (particularly race/ethnicity, education, systolic blood pressure, triglycerides, HDL, urine albumin to creatinine ratio, and years of diabetes duration) yielded results most similar to the ‘fully’ weighted results (Figure 1; eTables 7-8).

Figure 1:

Estimated benefit of intensive blood pressure treatment when weighting for different cardiovascular risk factorsDemographic characteristics weighting includes age, gender, race/ethnicity, education, and health insurance status. Clinical risk factors weighting includes smoking status, history of myocardial infarction, history of congestive heart failure, history of stroke, systolic blood pressure, diastolic blood pressure, high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), triglycerides, hemoglobin A1c, fasting plasma glucose, glomerular filtration rate, urinary albumin to creatinine ratio, and body mass index. Two models specifically explore the influence of factors that were particularly unbalanced when weighting for all factors. By weighting only for these subsets of factors, we can achieve better balance on them then when weighting for the totality of the factors. For these analyses, subset 1 includes race/ethnicity, education, systolic blood pressure, triglycerides, HDL, and urine albumin to creatinine ratio. Subset 2 adds years of diabetes duration to subset 1. Fully weighted includes all demographic characteristics and clinical risk factors.

Discussion

We sought to transport the results of the ACCORD BP trial to a population more representative of Americans with diabetes, and found that intensive BP therapy would be expected to be associated with lower risk for the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death, along with lower risk for stroke alone, in the general DM population. The estimated benefit of intensive treatment seen after re-weighting is in line with those observed in the SPRINT trial, which helps harmonize the results of the two studies.(5) These findings favor intensive BP treatment, but also highlight the lack of data support for blood pressure treatment guidance in large segments of the US adult population with diabetes mellitus--particularly racial/ethnic minorities and those with lower cardiovascular risk.

The magnitude of the estimated reduction in the primary outcome suggested a number needed to treat of 172 at one year and 34 at 5 years to avert one cardiovascular event. For reference, the ACC/AHA guidelines recommend treatment in those with a 10-year risk >10%, which will have a number needed to treat of around 300 at one year.(2, 24) Intensive therapy was also associated with reduced stroke incidence in weighted estimates, similar to unweighted estimates, but no difference in all-cause mortality or microvascular complications of diabetes. Intensive therapy was associated with a number needed to harm of 275 at 1 year.

These findings offer significant new contributions to the literature on blood pressure guidelines, and to the literature on the interpretation of clinical trial results more broadly. Current guidelines for BP treatment among patients with diabetes do not restrict their recommendations to those included in major trials, and vary notably in their target BP recommendations.(2) Guideline committees and individual practitioners do not have the luxury of waiting for a RCT that perfectly matches the general U.S. population or a particular patient panel before making treatment recommendations or decisions; since RCTs are expensive and time consuming, and it is sometimes difficult to enroll certain groups, attempting to generalize trial results among a selected participant population to a more real-world population is inevitable. This is not a criticism; in the absence of a directly applicable trial, the alternative to transporting results is not to use trial results at all. However, recent statistical advances have allowed us to transport results quantitatively and formally(7-9), rather than in an informal or qualitative way, which may help advise clinical practice guidelines and help inform practitioners faced with diverging guidelines.

Our work also informs the specific interpretation of the SPRINT and ACCORD BP trials. Prior work analyzing who benefits most from intensive BP treatment found that non-Hispanic Black race/ethnicity was associated with greater benefit.(25) Another reanalysis of ACCORD BP data found that, among a subset of ACCORD BP participants who would have been eligible for SPRINT (apart from DM), intensive BP treatment reduced a composite outcome of cardiovascular events.(26). Finally, prior work found that the relative benefit of treatment may be greater in those with lower, compared with higher, cardiovascular risk.(27) These results are all consistent with the current study, where we observed more relative benefits of intensive BP treatment when the overall risk was lower. Conversely, this finding does differ from a meta-analysis of blood pressure trials that did not find different relative risks associated with blood pressure treatment as cardiovascular risk varied.(24) However, that meta-analysis did not include ACCORD BP or SPRINT data. Further, sub-group analyses of ACCORD BP in the original manuscript(6) suggested larger benefits with intensive therapy in individuals with lower baseline HbA1c and lower diastolic blood pressure (though interaction terms were not significant). Since the US population with diabetes has lower HbA1c and blood pressure than the included sample, re-weighting the study likely emphasized the experience of those participants.

There are important limitations to our study. Transport methods can only standardize results over variables that have been measured. If data on important risk factors, such as social factors that may modify the effectiveness of therapy in the real-world, are not available, and differ between the original and transported population, then the results may not fully reflect what would happen if the intervention was applied to the new population. Design choices about who to include in the ACCORD sample also make it more difficult to apply results to the overall US population, as indicated by residual lack of balance for some factors. Because ACCORD BP specifically recruited individuals at high cardiovascular risk (higher than average for an individual with diabetes), there is poor overlap between ACCORD BP and the US population for some low risk groups. This leads to uncertainty in estimating the potential effects of intensive blood pressure control, and should prompt caution in interpreting the study results until they can be confirmed in samples that better match the overall U.S. population of adults with diabetes mellitus. Further, the publicly available data on serious adverse events does not make it possible to attribute specific adverse events to blood pressure (as opposed to glycemia) medications, or to conduct time-to-event analyses for this outcome.

The results of this study, in light of the new AHA/ACC guidelines(2), bring up the unanswered question of what to do when transported results qualitatively differ from those of the original trial. Given the novelty of transportability methods, we believe it is best to view the results of this study as hypothesis generating until more rigorous prospective validation of transportability methods, such as post-transportability clinical studies, enable us to formally assess outcomes among patients treated with and without clinical decisions informed by transportability analyses. Next, the residual imbalance between the weighted ACCORD BP and NHANES population does highlight areas where the evidence favoring intensive BP has less data support. To address this, we conducted sensitivity analyses adjusted for residual imbalance between the weighted ACCORD-BP and NHANES populations, and we used methods that were less sensitive to the unrepresentativeness of the ACCORD BP trial. In both cases, results were even more in favor of intensive BP therapy than our base case analysis; this suggests that residual confounding and lack of representativeness of the ACCORD BP trial are unlikely to explain our observed results. However, future studies should examine further the robustness of the intensive BP effect among racial/ethnic minorities with lower baseline cardiovascular risk, who were the least-informed by the ACCORD-BP results. This brings up an important gap in knowledge for future research: how much to transport results when data that directly answer the question have limited availability and require higher weighting of few individuals. Our results also suggest several more directions for future research. Analyses only weighting for demographics or cardiovascular risk alone had smaller changes than those accounting for both demographics and clinical risk factors, which suggests there may be some interaction between demographic and cardiovascular risk factors worth exploring when analyzing heterogeneous treatment effects, rather than relying only on univariate subgroup analyses.(28)

Overall, our study helps to make quantitative judgements regarding how to generalize trial results to a broader population. Additionally, the methods highlight the specific areas where existing evidence provides the most or least support. While lack of data in some groups means results supporting intensive BP treatment should be interpreted cautiously, it also highlights areas that need further study to better inform BP treatment guidelines.

Abbreviations

DM

Diabetes Mellitus

BP

Blood Pressure

AHA/ACCSystolic Blood

American Heart Association/American College of Cardiology

SPRINT

Pressure Intervention Trial

ACCORD

Action to Control Cardiovascular Risk in Diabetes

NHANES

National Health and Nutrition Examination Survey

MI

Myocardial Infraction

CHF

Congestive Heart Failure

HDL

High Density Lipoprotein

LDL

Low Density Lipoprotein

HbA1c

Hemoglobin A1c

FPG

Fasting Plasma Glucose

GFR

Glomerular Filtration Rate

MDRD

Modification of Diet in Renal Disease

BMI

Body Mass Index

HR

Hazard Ratio

95%CI

95% Confidence Interval

IRR

Incidence Rate Ratio